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71.
Peter J. Hosein Jocelyn C. Maragulia Matthew P. Salzberg Oliver W. Press Thomas M. Habermann Julie M. Vose Martin Bast Ranjana H. Advani Robert Tibshirani Andrew M. Evens Nahida Islam John P. Leonard Peter Martin Andrew D. Zelenetz Izidore S. Lossos 《British journal of haematology》2014,165(3):358-363
Primary breast diffuse large B‐cell lymphoma (DLBCL) is a rare subtype of non‐Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow‐up of 4·5 years (range 0·6–20·6 years), the Kaplan–Meier estimated median progression‐free survival was 10·4 years (95% confidence interval [CI] 5·8–14·9 years), and the median overall survival was 14·6 years (95% CI 10·2–19 years). Twelve patients (16%) had CNS relapse. A low stage‐modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage‐modified IPI score is associated with survival. 相似文献
72.
H. Raghuraman Shahidul M. Islam Soumi Mukherjee Benoit Roux Eduardo Perozo 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(5):1831-1836
In K+ channels, the selectivity filter, pore helix, and outer vestibule play a crucial role in gating mechanisms. The outer vestibule is an important structurally extended region of KcsA in which toxins, blockers, and metal ions bind and modulate the gating behavior of K+ channels. Despite its functional significance, the gating-related structural dynamics at the outer vestibule are not well understood. Under steady-state conditions, inactivating WT and noninactivating E71A KcsA stabilize the nonconductive and conductive filter conformations upon opening the activation gate. Site-directed fluorescence polarization of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled outer vestibule residues shows that the outer vestibule of open/conductive conformation is highly dynamic compared with the motional restriction experienced by the outer vestibule during inactivation gating. A wavelength-selective fluorescence approach shows a change in hydration dynamics in inactivated and noninactivated conformations, and supports a possible role of restricted/bound water molecules in C-type inactivation gating. Using a unique restrained ensemble simulation method, along with distance measurements by EPR, we show that, on average, the outer vestibule undergoes a modest backbone conformational change during its transition to various functional states, although the structural dynamics of the outer vestibule are significantly altered during activation and inactivation gating. Taken together, our results support the role of a hydrogen bond network behind the selectivity filter, side-chain conformational dynamics, and water molecules in the gating mechanisms of K+ channels.The functional behavior of K+ channels is defined by a series of structural rearrangements associated with the processes of activation and inactivation gating (1–6). In response to a prolonged stimulus and in the absence of an N-terminal inactivating particle, most K+ channels become nonconductive through a process known as C-type inactivation (7). This C-type inactivation is crucial in controlling the firing patterns in excitable cells and is fundamental in determining the length and frequency of the cardiac action potential (8). C-type inactivation is inhibited by high extracellular K+ (9, 10), and the blocker tetraethylammonium (TEA) (11) can also be slowed down in the presence of permeant ions with a long residence time in the selectivity filter (Rb+, Cs+, and NH4+) (10).The prokaryotic pH-gated K+ channel KcsA shares most of the mechanistic properties of C-type inactivation in voltage-dependent K+ channels (5, 6, 12–16). Recent crystal structures of open/inactivated KcsA reveal that there is a remarkable correlation between the degree of opening at the activation gate and the conformation and ion occupancy of the selectivity filter (5). In KcsA, the selectivity filter is stabilized by a hydrogen bond network, with key interactions between residues Glu71, Asp80, and Trp67 and a bound water molecule (17). Disrupting this hydrogen bond network favors the conductive conformation of the selectivity filter (12, 13, 15).Early electrophysiological experiments have suggested that the outer vestibule (around T449 residue in Shaker and Y82 residue in KcsA) undergoes significant conformational rearrangement during C-type inactivation gating (16, 18, 19). However, comparison of the WT KcsA crystal structure, where the filter is in its conductive conformation, with either the structure obtained with low K+ (collapsed filter) (17) or the crystal structure of open-inactivated KcsA with maximum opening (inactivated filter) (5) does not show major conformational changes in the outer vestibule that would explain these results (Fig. 1A). We have suggested that this apparent discrepancy can be understood if we take into consideration the potential differences in the dynamic behavior of the outer vestibule changes as the K+ channel undergoes its gating cycle (16).Open in a separate windowFig. 1.Comparison of outer vestibule conformation in KcsA structures with conductive and collapsed/inactivated filters. (A) High-K+ KcsA structure [Protein Data Bank (PDB) ID code 1K4C; yellow] is compared with a low-K+ KcsA structure (PDB ID code 1K4D; blue) in the closed state (Left) and open/inactivated conformation (PDB ID code 3F5W; green) (Right). The outer vestibule residues are depicted as red spheres, and relevant residues are labeled. (B) Schematic representation of typical macroscopic currents elicited by pH-jump experiments in WT (inactivating) and E71A (noninactivating) KcsA channels at a depolarizing membrane potential is shown. Conditions that stabilize the closed, open/inactivated, and open/conductive conformations at the steady state are indicated with a black circle. (C) Effect of opening the lower gate on the mobility of spin-labeled outer vestibule residues in palmitoyloleoylphosphatidyl choline/palmitoyloleoylphosphatidyl glycerol (POPC/POPG) (3:1, moles/moles) reconstituted WT (Left) and noninactivating mutant E71A (Right) backgrounds for the closed (pH 7, red) and open (pH 4, black) states of KcsA, as determined by continuous wave (CW) EPR. The spectra shown are amplitude-normalized. Details are provided in SI Materials and Methods.We have probed the gating-induced structural dynamics at the outer vestibule of KcsA using site-directed fluorescence and site-directed spin labeling and pulsed EPR approaches in combination with a recently developed computational method, restrained ensemble (RE) simulations. RE simulation was used to constrain the outer vestibule using experimentally derived distance histograms in different functional states (closed, open/inactivated, and open/conductive) and to monitor the extent of backbone conformational changes during gating. To this end, we took advantage of our ability to stabilize both the open/conductive (E71A mutant) and the open/inactivated (WT) conformations of KcsA upon opening the activation gate under steady-state conditions (Fig. 1B).Our data show that the outer vestibule in the open/conductive conformation is highly dynamic. In addition, the red edge excitation shift (REES) points to a change in hydration dynamics between conductive and nonconductive outer vestibule conformations, suggesting a role of restricted water molecules in C-type inactivation gating. We suggest that, on average, the backbone conformation of the outer vestibule does not change significantly between different functional states but that local dynamics change significantly, underlining the importance of the hydrogen bond network behind the selectivity filter and the microscopic observables (e.g., dynamics of hydration) in K+ channel gating and C-type inactivation. 相似文献
73.
Suhail A.R. Doi Luis Furuya‐Kanamori Egon Toft Omran A.H. Musa Nazmul Islam Justin Clark Lukman Thalib 《Obesity reviews》2020,21(1)
Previous randomized and observational studies on the efficacy of metformin in pregnancy to reduce incident gestational diabetes mellitus (GDM) in women at high risk (obesity, polycystic ovary syndrome [PCOS], or pregestational insulin resistance) have been conflicting and several groups are planning further randomized controlled trials (RCTs) to answer this question conclusively. This work assesses the efficacy of metformin in pregnancy to avert one outcome—incident GDM in women at high risk. We included RCTs comparing metformin with usual care or placebo controls in terms of incident GDM and recruiting women at high risk during early pregnancy. Eleven eligible trials enrolled 2370 adult women whose intervention arm consisted of metformin started at conception or before 20 weeks of gestation. Risk of GDM was similar in intervention compared with controls (risk ratio [RR] 1.03; 95% confidence interval [CI], 0.85‐1.24). The data were of sufficient quality meeting the criteria for consistency and directness. We conclude that metformin does not contribute to averting the GDM outcome in women at high risk when initiated in pregnancy. The evidence provided by this synthesis affirms that further broad clinical trials investigating this question are no longer needed. 相似文献
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79.
Shofiq Islam Muhiuddin AhmedGary M. Walton Timothy G. DinanGary R. Hoffman 《Journal of cranio-maxillo-facial surgery》2012,40(1):82-85
Aim
The potential psycho-social sequelae of traumatic facial injury have received increasing attention in recent years, however there remains paucity of cross-national comparative data on the prevalence of psychological distress following such trauma. The aim of the present study was to investigate and compare the prevalence of anxiety and depression in an adult patient group who have been treated for maxillofacial trauma, and who attend a follow-up clinic in either the West Midlands, UK or New South Wales (NSW), Australia. By using an identical methodological and statistical approach, we hoped to add to the available information on the incidence of early psychological distress in patients following facial trauma.Method
This was a comparative cross-sectional study. A sample of fifty consecutive adult victims of facial trauma in the West Midlands UK, was compared to a group of fifty-two facially injured patients in NSW, Australia. Demographic data was collected, following which the Hospital Depression and Anxiety Scale (HADS) were applied to both groups of patients.Results
Psychometric scores suggestive of anxiety and depressive state were common in both groups of patients. The mean HADS depression subscale score for UK patients compared to Australian patients was not significantly different (5.94 versus 5.54 p = 0.62). This was also the case for the HADS anxiety subscale (5.96 versus 5.94 p = 0.98). Although the number of patients achieving scores suggestive of a ‘caseness’ for co-morbid psychological state was higher within the UK sample when compared to the Australian group (20% versus 11.5% for HADS depression subscale, and 20% versus 15% for HADS anxiety subscales respectively); these differences did not reach statistical significance.Conclusion
This cross-national comparative study has shown that anxiety and depression in facial trauma victims were comparable in both settings. 相似文献80.
Elsherbiny IA 《Echocardiography (Mount Kisco, N.Y.)》2012,29(2):158-164
Background: Endothelial and microvascular dysfunction have been implicated in slow coronary flow (SCF). How and to what extent do these etiological factors affect left ventricular (LV) function and exercise capacity? Aim: The aim of the study was to evaluate LV systolic and diastolic function by pulsed tissue Doppler imaging (TDI) in SCF patients and their effects on exercise capacity. Subjects and methods: Sixty SCF patients and 20 control subjects were included in the study. Echocardiographic examination, treadmill exercise test, and TDI were performed. Isovolumic myocardial acceleration (IVA) and myocardial performance index (MPI) were measured. Results: TDI mean parameters for systolic and diastolic LV function were significantly impaired in SCF group with decreased Sa, IVA, Ea/Aa, and increased MPI (0.31 ± 0.06 vs. 0.26 ± 0.04, P < 0.01) compared to control. There was significant correlation between thrombolysis in myocardial infarction (TIMI) frame count and TDI mean parameters for LV systolic function (Sa & IVA, r =?0.53, P < 0.01 & r =?0.36, P < 0.05, respectively). Mean TIMI frame count was correlated with MPI and E/Ea. SCF patients had poorer peak exercise capacity than the controls (9.9 ± 1.9 METs vs. 12.7 ± 2.3, P < 0.01) with significant negative correlation with mean TIMI frame count (r =?0.46, P < 0.01). Conclusion: There is impairment of LV systolic and diastolic function in SCF patients with clinical impact on exercise capacity which emphasizes the importance of close follow‐up of these patients for risk stratification. (Echocardiography 2012;29:158‐164) 相似文献